Dayoub Rania, Buerger Leonhard, Ibrahim Sara, Melter Michael, Weiss Thomas S
University Children's Hospital Regensburg (KUNO), University Hospital Regensburg, Germany; Department of Biochemistry and Microbiology, Faculty of Pharmacy, Damascus University, Damascus, Syria.
University Children's Hospital Regensburg (KUNO), University Hospital Regensburg, Germany.
Exp Mol Pathol. 2017 Jun;102(3):428-433. doi: 10.1016/j.yexmp.2017.05.011. Epub 2017 May 12.
The acute-phase response (APR) is an inflammatory process triggered mainly by IL-6 in response to neoplasm, tissue injury, infection or inflammation. Signaling of IL-6 is transduced by activating STAT3 which rapidly results in production of acute-phase proteins (APPs) such as fibrinogen β (FGB) and haptoglobin (HP). Augmenter of liver regeneration (ALR), a hepatotrophic factor supporting liver regeneration, was reported to be upregulated after liver damage. In this study we analyzed the role of ALR for IL-6 signaling and APR. Thus, we investigated the expression and release of APPs in human liver cells under conditions of increased exogenous or endogenous ALR. HepG2 cells and ALR-reexpressing HepG2 cells were treated with IL-6 in the presence or absence of exogenous ALR for different time points. The mRNA expression and release of both FGB and HP were measured by RT-PCR and ELISA. We found that exogenously applied ALR attenuated the IL-6-induced mRNA expression and protein secretion of both FGB and HP. In contrast, IL-6 stimulation in HepG2 cells which re-express ALR, revealed elevated APR shown by increased mRNA expression and secretion of FGB and HP. Furthermore, we found that ALR-mediated regulation of IL-6-induced APP production is accompanied by altered STAT3 activity. While exogenous ALR reduced the IL-6-induced phosphorylation of STAT3, endogenous ALR enhanced STAT3 activity in liver cells. In conclusion, ALR, dependent on its localization, changes APR at least in part, by modifying STAT3 activation. This study shows a dual signaling of ALR and suggests that ALR is pivotal for the regulation of APR, a crucial event in liver injury and regeneration.
急性期反应（APR）是一种主要由白细胞介素-6（IL-6）触发的炎症过程，以应对肿瘤、组织损伤、感染或炎症。IL-6的信号通过激活信号转导和转录激活因子3（STAT3）进行转导，这会迅速导致急性期蛋白（APPs）的产生，如纤维蛋白原β（FGB）和触珠蛋白（HP）。肝脏再生增强因子（ALR）是一种支持肝脏再生的肝营养因子，据报道在肝脏损伤后会上调。在本研究中，我们分析了ALR在IL-6信号传导和APR中的作用。因此，我们研究了在增加外源性或内源性ALR的条件下，人肝细胞中APPs的表达和释放。在存在或不存在外源性ALR的情况下，用IL-6处理HepG2细胞和重新表达ALR的HepG2细胞不同时间点。通过逆转录聚合酶链反应（RT-PCR）和酶联免疫吸附测定（ELISA）测量FGB和HP的mRNA表达和释放。我们发现外源性应用的ALR减弱了IL-6诱导的FGB和HP的mRNA表达和蛋白质分泌。相反，在重新表达ALR的HepG2细胞中进行IL-6刺激，显示出急性期反应增强，表现为FGB和HP的mRNA表达和分泌增加。此外，我们发现ALR介导的对IL-6诱导的APP产生的调节伴随着STAT3活性的改变。虽然外源性ALR降低了IL-6诱导的STAT3磷酸化，但内源性ALR增强了肝细胞中的STAT3活性。总之，ALR根据其定位，至少部分地通过改变STAT3激活来改变急性期反应。本研究显示了ALR的双重信号传导，并表明ALR对于急性期反应的调节至关重要，而急性期反应是肝脏损伤和再生中的关键事件。
